CN102993087A - Impurity compound in Tegafur/Gimeracil/Oteracil prescription, and preparation method and application thereof - Google Patents
Impurity compound in Tegafur/Gimeracil/Oteracil prescription, and preparation method and application thereof Download PDFInfo
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- 239000012535 impurity Substances 0.000 title claims abstract description 92
- 150000001875 compounds Chemical class 0.000 title claims abstract description 88
- 238000002360 preparation method Methods 0.000 title claims abstract description 51
- MREOOEFUTWFQOC-UHFFFAOYSA-M potassium;5-chloro-4-hydroxy-1h-pyridin-2-one;4,6-dioxo-1h-1,3,5-triazine-2-carboxylate;5-fluoro-1-(oxolan-2-yl)pyrimidine-2,4-dione Chemical compound [K+].OC1=CC(=O)NC=C1Cl.[O-]C(=O)C1=NC(=O)NC(=O)N1.O=C1NC(=O)C(F)=CN1C1OCCC1 MREOOEFUTWFQOC-UHFFFAOYSA-M 0.000 title abstract description 5
- 239000013558 reference substance Substances 0.000 claims abstract description 32
- 239000000126 substance Substances 0.000 claims abstract description 25
- 238000007689 inspection Methods 0.000 claims abstract description 3
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 claims description 35
- 229960001674 tegafur Drugs 0.000 claims description 35
- 239000000243 solution Substances 0.000 claims description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 18
- 230000014759 maintenance of location Effects 0.000 claims description 15
- 239000012071 phase Substances 0.000 claims description 14
- 238000001514 detection method Methods 0.000 claims description 13
- ZPLQIPFOCGIIHV-UHFFFAOYSA-N Gimeracil Chemical compound OC1=CC(=O)C(Cl)=CN1 ZPLQIPFOCGIIHV-UHFFFAOYSA-N 0.000 claims description 12
- 238000012360 testing method Methods 0.000 claims description 12
- RYYCJUAHISIHTL-UHFFFAOYSA-N 5-azaorotic acid Chemical compound OC(=O)C1=NC(=O)NC(=O)N1 RYYCJUAHISIHTL-UHFFFAOYSA-N 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 229950009822 gimeracil Drugs 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 229950000193 oteracil Drugs 0.000 claims description 11
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 239000011541 reaction mixture Substances 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 9
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 9
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- 239000000377 silicon dioxide Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
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- 238000005374 membrane filtration Methods 0.000 claims description 5
- 230000035945 sensitivity Effects 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 claims description 4
- 238000010812 external standard method Methods 0.000 claims description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methyl alcohol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 4
- 239000002953 phosphate buffered saline Substances 0.000 claims description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 12
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- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 13
- 229960002949 fluorouracil Drugs 0.000 description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- 231100000331 toxic Toxicity 0.000 description 9
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- 102100022334 Dihydropyrimidine dehydrogenase [NADP(+)] Human genes 0.000 description 6
- 108010066455 Dihydrouracil Dehydrogenase (NADP) Proteins 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
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- 238000006555 catalytic reaction Methods 0.000 description 4
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- 239000001301 oxygen Substances 0.000 description 4
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- 125000003118 aryl group Chemical group 0.000 description 3
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- 229940079593 drug Drugs 0.000 description 3
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- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 2
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 2
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- 229960005010 orotic acid Drugs 0.000 description 2
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- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 1
- HFEKDTCAMMOLQP-RRKCRQDMSA-N 5-fluorodeoxyuridine monophosphate Chemical compound O1[C@H](COP(O)(O)=O)[C@@H](O)C[C@@H]1N1C(=O)NC(=O)C(F)=C1 HFEKDTCAMMOLQP-RRKCRQDMSA-N 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- NKCSETJJPUIIJO-UHFFFAOYSA-N OCCCC(c(c(O)c(cn1)Cl)c1O)c(c(O)ncc1Cl)c1O Chemical compound OCCCC(c(c(O)c(cn1)Cl)c1O)c(c(O)ncc1Cl)c1O NKCSETJJPUIIJO-UHFFFAOYSA-N 0.000 description 1
- WFWLQNSHRPWKFK-UHFFFAOYSA-N Tegafur Chemical compound O=C1NC(=O)C(F)=CN1C1OCCC1 WFWLQNSHRPWKFK-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
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- 229910052801 chlorine Inorganic materials 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
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- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
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Abstract
The invention discloses a compound shown in Formula IV, and also discloses a preparation method of the compound and application of the compound used as an impurity reference substance in the inspection process of related substances of a Tegafur/Gimeracil/Oteracil preparation. Through the implementation of the invention, the quality of the Tegafur/Gimeracil/Oteracil preparation can be effectively controlled, thereby ensuring the safety and effectiveness of the Tegafur/Gimeracil/Oteracil preparation in the clinical use.
Description
Technical field
The invention belongs to medical technical field, relate to impurity compound and preparation method and purposes in a kind of Tegafur, gimeracil, the oteracil potassium prescription, relate in particular to impurity compound 4, when 4-two (6,10-dihydroxyl-7-chloro-pyridyl)-propyl carbinol and preparation method thereof and quality control as the purposes of impurity reference substance.
Background technology
, formed according to 1: 0.4: 1 ratio of mol ratio by Tegafur, gimeracil and 3 kinds of compositions of oteracil potassium the earliest by the development listing of Japanese Taiho Pharmaceutical Co. Ltd for lucky Austria.Entered clinical stage in 1994, be approved for the treatment of late gastric cancer in 1999, with its good antitumous effect, lower toxic side effect, promoted gradually the treatment that is used for above-mentioned all kinds of cancers, 2004 recommended combination with cisplatin (CDDP) as curing gastric cancer general planning, mainly contain capsule and tablet for lucky formulation difficult to understand at present.
For lucky capsule difficult to understand, claim again S-1, TS-1 capsule, be the compound anti-cancer medicine that a kind of effective constituent is comprised of Tegafur, gimeracil, oteracil potassium, be widely used in the treatment of the tumor diseases such as late gastric cancer, incidence cancer, colorectal carcinoma, nonsmall-cell lung cancer, metastatic breast cancer and carcinoma of the pancreas at present.
Tegafur (FT, FT207) is one of miazines anticarcinogen, and structural formula is as follows:
It is the prodrug of 5 FU 5 fluorouracil (5-FU), and most solid tumors are had restraining effect.In vivo competent biosynthesizing of disturbing blocking dna, RHA and protein, thus its antitumous effect produced.
Gimeracil (CDHP) structural formula II and oteracil potassium (OXO) structural formula II I use separately respectively and do not have obvious antitumour activity, they and Tegafur to unite to use is in order to improve curative effect and to reduce toxicity.
The effect of CDHP is for improving the anticancer therapeutic of FT, when FT is oral enter in the body after, at first under the catalysis of liver P450 activating enzymes, be transformed into 5-FU, except about 10%, enter afterwards enteron aisle and under vitamin B13 ribose transferring enzyme (ORTC) catalysis, produce the phosphorylation, all the other 5-FU of about 90% are under the catalysis of liver dihydropyrimidine dehydrogenase (DPD), and the approach that follows 5-FU is transformed into triphosphoric acid floxuridine (FUTP) and two active result performances of a phosphoric acid doxifluridine (FdUMP) antitumous effect.So DPD is the main rate-limiting enzyme of 5-FU degraded, the maintenance of its blood plasma 5-FU level depends on that DPD is active.CDHP is the reversible inhibitor of DPD.Through comparing, the effect of CDHP inhibition DPD activity is 180 times of uridylic, thereby the degraded of energy establishment 5-FU.Experiment showed, as CDHP: when FT cooperates with 0.4: 1 (M), the interior 5-FU level of significance of tumor tissues was kept more than 12 hours, the toxic side effects of enteron aisle is increased.The Main Function of oteracil potassium is the activity that suppresses the ORTC of small intestine.In the metabolic process of Tegafur, there is the 5-FU about 10% to enter intestinal tissue, under the catalysis of vitamin B13 ribose transferring enzyme, produce phosphorylation, this process is considered to produce the major cause of enteron aisle toxic side effect.The another one outstanding feature of OXO be oral enter in the body after, the overwhelming majority is distributed in the small intestinal cell surface, enters blood circulation, tumor tissues and other healthy tissuess when only having few part.Therefore, OXO mainly suppresses the effect of 5-FU phosphorylation in small intestine, can not affect the activity of 5-FU in tumor tissues.When OXO: FT (M) is 1: 1, can keep higher tumor killing effect, reduction enteron aisle toxic side effects that again can be by a relatively large margin.
In new drug research and the performance history, the quality of medicine is to weigh a major criterion of medicine quality, and the quality of medicine at first is decided by curative effect and the toxic side effect of medicine self, the i.e. validity of medicine and security.What the curative effect of medicine and side effect reflected is the inner quality of medicine, and the weak curative effect of a medicine does not reach the purpose of curing the disease, and does not no doubt have clinical value; Even and a medicine good effect, if but toxicity or side effect are very large, also be not useable for clinically, therefore require medicine in the scope for the treatment of, do not produce serious toxic reaction, do not produce or less having side effects.
The content of the effective constituent of medicine is the important symbol of reflection pharmaceutical purity, and the impurity that exists in the medicine directly has influence on the generation that the curative effect of medicine also may cause toxic side effect.The impurity of medicine be produce, other chemical substance beyond the medicine of the introduction in the storage and transport process or generation, the existence of impurity not only affects the purity of medicine, also can bring the toxic side effect of non-therapeutic activity, must be controlled.
For using safely and effectively medicine, the quality standard of medicine has comparatively strict regulation to the purity of effective ingredient and the limit of impurity, and generally speaking, surpassing 0.1% impurity of the drug should identify and quantitatively by process for selective.
Summary of the invention
The invention provides impurity compound 4 in a kind of Tegafur, gimeracil, oteracil potassium (hereinafter to be referred as for the lucky difficult to understand) prescription, when 4-two (6,10-dihydroxyl-7-chloro-pyridyl)-propyl carbinol and preparation method thereof and quality control as the purposes of impurity reference substance.
The contriver finds through a large amount of analysis and research, replacing lucky combination preparation difficult to understand is to the environment pH value, humidity, light, carbonic acid gas, pharmaceutically active substances with the oxygen sensitivity, in the process that stores, can produce a kind of impurity compound for lucky agent agent difficult to understand, in preparation, show a rising trend under this impurity compound certain condition, though not yet grasp its detailed pharmacology or toxicity data at present, the contriver is by to carrying out a large amount of research for lucky difficult to understand each component drug physico-chemical property and interaction mechanism thereof, grope to prepare the separating technology route, optimize preparation parameter and obtain this compound, and thereby its experiment data analysis confirmed the structure of this compound, by structural analysis, the contriver thinks that this impurity is that Tegafur and the mutual chemical combination covalent attachment of gimeracil molecule generation molecular transposition form, and concrete impurity formation mechanism is as follows:
Content and the ratio of effective constituent have been reduced for the generation of lucky impurity compound difficult to understand, affected to a certain extent the curative effect of medicine, and probably cause the toxic side effect of non-therapeutic, therefore, understanding to this new drug impurity compound characteristic, the usefulness that understanding impurity can affect security and medicine is important, and has an opportunity to finish the sign of the impurity effect factor, toxicologic study, and it can be used for analyzing the impurity standard for lucky finished dosage forms difficult to understand.
The present invention for lucky impurity compound chemical name difficult to understand is: 4,4-two (6,10-dihydroxyl-7-chloro-pyridyl)-propyl carbinol has as shown in the formula structure shown in (IV):
By mass spectrum (MS) and nucleus magnetic resonance (NMR) wave spectrum this compound is carried out structural characterization, then carry out mass spectrum (MS), nucleus magnetic resonance (NMR) wave spectrum and data analyses such as infrared (IR), the below is described this impurity compound chemical feature parameter.
One, high resolution mass spectrum:
High resolution mass spectrum provides molecule C
14H
14Cl
2N
2O
5[M-H]
-Molecular ion peak, measured value are 359.0206, and calculated value is: 359.0212, and calculating degree of unsaturation is 8.
Two, infrared spectra
3573.58cm
-1There is strong absorption peak at the place, is attributed to intermolecular hydroxyl hydrogen bond (O-H) absorption peak of association
3233.97cm
-1The middle intensity absorption peak at place is attributed to hydroxyl (O-H) absorption peak
3090.98cm
-1The middle intensity absorption peak at place is attributed to (=C-H) stretching vibration absorption peak
1635.92～1439.66cm
-1The serial absorption peak at place is attributed to the pyridine ring characteristic peak
1232.78 and 1257.55cm
-1Absorption peak, be attributed to (C-O) stretching vibration absorption peak of phenolic hydroxyl group
1052.68cm
-1Weak absorption peak, be attributed to (C-O) stretching vibration absorption peak of primary alconol
867.10cm
-1Strong absorption peak is arranged, and pyridine ring is that four replacements only have a hydrogen
Three, UV spectrum
In UV spectrum, we can see at the 212nm place maximum absorption band, can be attributed to the K absorption band of aromatic ring.Absorption peak at the 294nm place can be attributed to the B band absorption peak after aromatic nucleus produces red shift since introduce auxochromous group-OH and-Cl, and make aromatic ring B band absorption peak produce red shift.
Four, nuclear-magnetism
The one dimension nuclear magnetic spectrogram:
1H-NMR spectrum signal [δ 14.100 (1H, s), 12.376 (2H, s), (7.745 1H, s), 7.695 (1H, s), 4.457 (1H, t, J=7.2Hz), 3.406 (2H, t, J=6.0Hz), 2.368 (1H d, J=6.6Hz), (2.303 1H, d, J=6.6Hz)].By observing
1The H-NMR spectrogram is found, may contain the phenolic hydroxyl group 14.100 (1H, s) that forms intermolecular hydrogen bonding in the compound, contains in addition two phenolic hydroxyl groups 12.376 (2H, s), also has an even CH of oxygen
2(3.406 2H, t, J=6.0Hz).
13C-NMR, DEPT spectrum signal [δ 165.188C, 164.333C, 162.712C, 162.499C, 132.155CH, 131.571CH, 114.475C, 114.388C, 109.070C, 108.521C, 60.346CH
2, 32.699CH, 31.700CH
2, 23.476CH
2].By observing
13C-NMR, DEPT From Spectral Signal, the carbon signal of low place finds that 10 carbon all are paired, and four even two key quaternary carbons of oxygen are wherein arranged, two key quaternary carbons of two company's chlorine, high field region contain an even oxygen CH
2(60.346CH
2).
Two dimension nuclear magnetic spectrogram: in the HMQC spectrogram: the corresponding 31.700CH of δ 1.346 (2H, t, J=6.6Hz)
2, 2.368 (1H, d, J=6.6Hz), the corresponding 23.476CH of 2.303 (1H, d, J=6.6Hz)
2, the corresponding 60.346CH of 3.406 (2H, t, J=6.0Hz)
2, the corresponding 32.699CH of 4.457 (1H, t, J=7.2Hz), the corresponding 131.571CH of 7.695 (1H, s), the corresponding 132.155CH of 7.745 (1H, s).
1H-
1HCOSY From Spectral Signal: δ 1.346 (2H, t, J=6.6Hz) and 3.406 (2H, t, J=6.0Hz), 2.368 (1H, d, J=6.6Hz), 2.303 (1H, d, J=6.6Hz) and 4.457 (1H, t, J=7.2Hz), 1.346 (2H, t, J=6.6Hz) relevant, 3.406 (2H, t, J=6.0Hz) have relevant with 1.346 (2H, t, J=6.6Hz), (4.457 1H, t, J=7.2Hz) and 2.368 (1H, d, J=6.6Hz), 2.303 (1H, d, J=6.6Hz) relevant.Following fragment is arranged:
δ 23.476CH in HMBC
2With 4.457 (1H, t, J=7.2Hz), 3.406 (2H, t, J=6.0Hz), 1.346 (2H, t, J=6.6Hz) are relevant, δ 31.700CH
2With 4.457 (1H, t, J=7.2Hz), (3.406 2H, t, J=6.0Hz), (2.368 1H, d, J=6.6Hz), 2.313 (1H, d, J=6.6Hz) is relevant, δ 32.699CH and 3.406 (2H, t, J=6.0Hz), (2.368 1H, d, J=6.6Hz), (2.303 1H, d, J=6.6Hz), 1.346 (2H, t, J=6.6Hz) is relevant, δ 132.155CH, 131.571CH and 4.457 (1H, t, J=7.2Hz) relevant, δ 162.499C and 7.695 (1H, s) are relevant, δ 162.712C and 7.745 (1H, s) are relevant, δ 164.333C and 7.745 (1H, s) relevant, δ 165.188C and 7.695 (1H, s) are relevant.Relevant according to HMBC, following fragment is arranged:
According to two-dimentional nuclear magnetic spectrogram the gained segment is coupled together, the structure that obtains compound is:
By compound is resolved, this compound molecular weight is 360, contain two chlorine atoms, molecular ion peak 359: 361: 363=9 has appearred in high resolution: 6: 1, meet the feature that contains two chlorine atoms, two pyridine rings arranged, have-OH and-the Cl auxochromous group, so that compound produces red shift, meet UV spectrum.Two quaternary pyridine rings are arranged, and the phenolic hydroxyl group of hydrogen bond between formed elements has free phenolic hydroxyl group, also has a primary hydroxyl, meets all diffuse reflectance infrared spectroscopies.The pyridine ring that two almost symmetries are arranged, so have 10 carbon that occur in pairs in low place, it is 12.376ppm that the hydroxyl hydrogen chemical shift of 10 and 10 ' position is arranged, two hydroxyls of 6 and 6 ' position, can form intermolecular hydrogen bonding, an exposed Hydrochemistry displacement outside is 14.100ppm, meets relevant nuclear magnetic spectrogram feature.
In sum, the contriver determines that this compound is: 4,4-two (6,10-dihydroxyl-7-chloro-pyridyl)-propyl carbinol, and each position C, the ownership of H chemical shift such as following table:
The invention still further relates to this for lucky impurity compound 4 difficult to understand, 4-two (6,10-dihydroxyl-7-chloro-pyridyl)-preparation method of propyl carbinol, the method comprises the following step: a, with Tegafur, gimeracil, oteracil potassium as reaction-ure mixture, 50-60 soluble in water ℃ stirring reaction 12-72 hour, by HPLC and HPLC-MS analysis monitoring reaction process, react complete solvent evaporated, get the white solid thing;
B, a is reacted the solid resultant use the preparation of preparation type (P-HPLC) liquid phase systems, removing foreign matter compound from reaction mixture.
Preferred Tegafur among the step a: gimeracil: oteracil potassium=1: 0.8～1.5: 0～1.2, mass volume ratio: reaction mixture: water=1g: 20-30ml.
Chromatographic condition and system suitability among the step b: with dynamic axial compression chromatographic column system (internal diameter 80mm), take octadecylsilane chemically bonded silica as weighting agent; Take water-acetonitrile (7: 3) as moving phase; The detection wavelength is 280nm; Flow velocity is 200ml/min; Theoretical plate number is calculated by the naphthalene peak and is not less than the 6000/25cm effective column length;
Get for lucky sample crude product difficult to understand, take by weighing 15g, put in the 2000ml beaker, measure 1000ml moving phase, jolting makes dissolving, and with 0.45 μ m membrane filtration, getting filtrate is sample to be separated.Each sample introduction 100ml gathers color atlas, and retention time is by the peak of 6.79min and is wanted impurity peaks, the liquid of collection 600mV 600mV to the peak before the peak, and concentrate drying gets the target impurity pure compounds.
The invention provides a kind of for lucky impurity compound 4 difficult to understand, the purposes of 4-two (6,10-dihydroxyl-7-chloro-pyridyl)-propyl carbinol, when being the inspection for lucky preparation related substance difficult to understand as the impurity reference substance.It can be used for analyzing for lucky combination preparation difficult to understand, is quality control and the stability analysis of finished product, as reference standard.
The preparation of need testing solution: lucifuge operation, get the development of preparation content, mix, precision takes by weighing in right amount (being equivalent to approximately Tegafur 50mg), put in the 100ml measuring bottle, add acetonitrile-water (3: 7) 30ml, ultrasonic 5min (temperature control on the rocks) takes out and is placed to room temperature, add acetonitrile-water (3: 7) to scale, shake up, filter, get subsequent filtrate as trial-product (facing with now joining).
The preparation of reference substance solution: get the about 14.5mg of impurity compound reference substance, the about 50mg of Tegafur reference substance, accurately weighed, put in the 100ml measuring bottle, add acetonitrile-water (3: 7) and dissolve and be diluted to scale, shake up; Precision is measured 1ml, puts in the 100ml measuring bottle, adds acetonitrile-water (3: 7) and dissolves and be diluted to scale, shakes up, in contrast product solution.
Chromatographic condition: be weighting agent with octadecylsilane chemically bonded silica, take phosphate buffered saline buffer-methyl alcohol (60: 40) as moving phase, the detection wavelength is 220nm, column temperature: 35 ℃, the resolution of Tegafur and impurity compound chromatographic peak is not less than 10.0; Get reference substance solution 15 μ l injection liquid chromatographies, regulate detection sensitivity, make the peak height of the chromatographic peak of impurity compound be about the 20%-25% of full range, precision is measured need testing solution and each 15 μ l of reference substance solution again, the injection liquid chromatography, the record color atlas is to 3 times of impurity compound chromatographic peak retention time, in the color atlas of need testing solution if any impurity peaks, take impurity compound as reference substance, press external standard method with calculated by peak area, impure compound must not be greater than 0.5% of Tegafur labelled amount, and containing retention time with respect to impurity compound and be 2.0 impurity must not be greater than 0.5% of Tegafur labelled amount.
Technique effect of the present invention is: the invention discloses for lucky combination preparation difficult to understand and producing, a kind of important impurity compound 4 that produces in the storage and transport process, 4-two (6,10-dihydroxyl-7-chloro-pyridyl)-propyl carbinol, the content of this impurity compound what directly affect the medicine quality of replacing lucky combination preparation difficult to understand, the present invention is directed to for lucky each component drug physico-chemical property difficult to understand and interaction mechanism thereof and carry out a large amount of research, grope to prepare the separating technology route, optimize preparation parameter and obtain this compound, and thereby its experimental data carried out the structure that this compound is confirmed in spectroscopic analysis, and prove that it is the major impurity for lucky preparation difficult to understand, 4,4-two (6,10-dihydroxyl-7-chloro-pyridyl)-the impurity reference substance of propyl carbinol when detecting for lucky preparation related substance difficult to understand, can be effectively, monitoring is for the related substance in the lucky preparation difficult to understand easily, the quality for lucky preparation difficult to understand has effectively been controlled in enforcement of the present invention, thereby guarantees security and validity for the clinical use of lucky preparation difficult to understand.
Description of drawings
Fig. 1 is for lucky impurity compound 4 difficult to understand, 4-two (6,10-dihydroxyl-7-chloro-pyridyl)-propyl carbinol
1The H-NMR spectrogram
Fig. 2 is for lucky impurity compound 4 difficult to understand, the IR spectrogram of 4-two (6,10-dihydroxyl-7-chloro-pyridyl)-propyl carbinol
Fig. 3 is for lucky impurity compound 4 difficult to understand, 4-two (6,10-dihydroxyl-7-chloro-pyridyl)-propyl carbinol
13The C-NMR spectrogram
Fig. 4 is for lucky impurity compound 4 difficult to understand, the UV spectrogram of 4-two (6,10-dihydroxyl-7-chloro-pyridyl)-propyl carbinol
Embodiment
Embodiment 1 is for lucky impurity compound 4 difficult to understand, the preparation of 4-two (6,10-dihydroxyl-7-chloro-pyridyl)-propyl carbinol
A, with Tegafur: gimeracil: oteracil potassium=1: 1: 1 is as reaction-ure mixture, it is soluble in water that (reaction mixture: water=1g: 20ml) 50 ℃ of stirring reactions are 72 hours, by HPLC and HPLC-MS analysis monitoring reaction process, react complete solvent evaporated, get white crude product solids;
B, will react the solid resultant and use the preparation of preparation type (P-HPLC) liquid phase systems, removing foreign matter compound from reaction mixture; Chromatographic condition and system suitability: with dynamic axial compression chromatographic column system (internal diameter 80mm), take octadecylsilane chemically bonded silica as weighting agent; Take water-acetonitrile (7: 3) as moving phase; The detection wavelength is 280nm; Flow velocity is 200ml/min; Theoretical plate number is calculated by the naphthalene peak and is not less than the 6000/25cm effective column length;
Get for lucky sample crude product difficult to understand, take by weighing 15g, put in the 2000ml beaker, measure 1000ml moving phase, jolting makes dissolving, and with 0.45 μ m membrane filtration, getting filtrate is sample to be separated.Each sample introduction 100ml gathers color atlas, and retention time is by the peak of 6.79min and is wanted impurity peaks, the liquid of collection 600mV 600mV to the peak before the peak, and concentrate drying gets the target impurity pure compounds.
Embodiment 2 is for lucky impurity compound 4 difficult to understand, the preparation of 4-two (6,10-dihydroxyl-7-chloro-pyridyl)-propyl carbinol
A, with Tegafur: gimeracil=1: 1 is as reaction-ure mixture, be dissolved in the reaction mixture water that (reaction mixture: water=1g: 20ml) 60 ℃ of stirring reactions are 48 hours, by HPLC and HPLC-MS analysis monitoring reaction process, react complete solvent evaporated, get white crude product solids;
B, will react the solid resultant and use the preparation of preparation type (P-HPLC) liquid phase systems, removing foreign matter compound from reaction mixture; Chromatographic condition and system suitability: with dynamic axial compression chromatographic column system (internal diameter 80mm), take octadecylsilane chemically bonded silica as weighting agent; Take water-acetonitrile (7: 3) as moving phase; The detection wavelength is 280nm; Flow velocity is 200ml/min; Theoretical plate number is calculated by the naphthalene peak and is not less than the 6000/25cm effective column length;
Get for lucky sample crude product difficult to understand, take by weighing 15g, put in the 2000ml beaker, measure 1000ml moving phase, jolting makes dissolving, and with 0.45 μ m membrane filtration, getting filtrate is sample to be separated.Each sample introduction 100ml gathers color atlas, and retention time is by the peak of 6.79min and is wanted impurity peaks, the liquid of collection 600mV 600mV to the peak before the peak, and concentrate drying gets the target impurity pure compounds.
Embodiment 3 is for lucky impurity compound 4 difficult to understand, the preparation of 4-two (6,10-dihydroxyl-7-chloro-pyridyl)-propyl carbinol
A, with Tegafur: gimeracil: oteracil potassium=1: 1.5: 1.2 is as reaction-ure mixture, it is soluble in water that (reaction mixture: water=1g: 30ml) 60 ℃ of stirring reactions are 48 hours, by HPLC and HPLC-MS analysis monitoring reaction process, react complete solvent evaporated, get white crude product solids;
B, will react the solid resultant and use the preparation of preparation type (P-HPLC) liquid phase systems, removing foreign matter compound from reaction mixture; Chromatographic condition and system suitability: with dynamic axial compression chromatographic column system (internal diameter 80mm), take octadecylsilane chemically bonded silica as weighting agent; Take water-acetonitrile (7: 3) as moving phase; The detection wavelength is 280nm; Flow velocity is 200ml/min; Theoretical plate number is calculated by the naphthalene peak and is not less than the 6000/25cm effective column length;
Get for lucky sample crude product difficult to understand, take by weighing 15g, put in the 2000ml beaker, measure 1000ml moving phase, jolting makes dissolving, and with 0.45 μ m membrane filtration, getting filtrate is sample to be separated.Each sample introduction 100ml gathers color atlas, and retention time is by the peak of 6.79min and is wanted impurity peaks, the liquid of collection 600mV 600mV to the peak before the peak, and concentrate drying gets the target impurity pure compounds.
Through confirming, embodiment 1,2,3 minutes the target compound structure identical, have following characteristic parameter:
EI-MS(m/z)＝359.0212[M-H]
-。
1H-NMR(600MHz，DMSO)[δ14.100(1H，s)，12.376(2H，s)，7.745(1H，s)，7.695(1H，s)，4.457(1H，t，J＝7.2Hz)，3.406(2H，t，J＝6.0Hz)，2.368(1H d，J＝6.6Hz)，2.303(1H，d，J＝6.6Hz)]。
13C-NMR(150MHz，DMSO)[δ165.188C，164.333C，162.712C，162.499C，132.155CH，131.571CH，114.475C，114.388C，109.070C，108.521C，60.346CH
2，32.699CH，31.700CH
2，23.476CH
2]。
Embodiment 4 impurity compounds 4,4-two (6,10-dihydroxyl-7-chloro-pyridyl)-propyl carbinol is measured the related substance that replaces lucky preparation difficult to understand as the reference substance of related substance
Replace lucky capsule related substance quality standard difficult to understand:
The preparation of need testing solution: lucifuge operation, get the development of preparation content, mix, precision takes by weighing in right amount (being equivalent to approximately Tegafur 50mg), put in the 100ml measuring bottle, add acetonitrile-water (3: 7) 30ml, ultrasonic 5min (temperature control on the rocks) takes out and is placed to room temperature, add acetonitrile-water (3: 7) to scale, shake up, filter, get subsequent filtrate as trial-product (facing with now joining).
Get the about 14.5mg of impurity compound reference substance, the about 50mg of Tegafur reference substance, accurately weighed, put in the 100ml measuring bottle, add acetonitrile-water (3: 7) and dissolve and be diluted to scale, shake up; Precision is measured 1ml, puts in the 100ml measuring bottle, adds acetonitrile-water (3: 7) and dissolves and be diluted to scale, shakes up, in contrast product solution.
Chromatographic condition: be weighting agent with octadecylsilane chemically bonded silica, take phosphate buffered saline buffer-methyl alcohol (60: 40) as moving phase, the detection wavelength is 220nm, column temperature: 35 ℃, the resolution of Tegafur and impurity compound chromatographic peak is not less than 10.0; Get reference substance solution 15 μ l injection liquid chromatographies, regulate detection sensitivity, make the peak height of the chromatographic peak of impurity compound be about the 20%-25% of full range, precision is measured need testing solution and each 15 μ l of reference substance solution again, the injection liquid chromatography, the record color atlas is to 3 times of impurity compound chromatographic peak retention time, in the color atlas of need testing solution if any impurity peaks, take impurity compound as reference substance, press external standard method with calculated by peak area, impure compound must not be greater than 0.5% of Tegafur labelled amount, and containing retention time with respect to impurity compound and be 2.0 impurity must not be greater than 0.5% of Tegafur labelled amount.
Impurity compound is measured for its related substances check result of lucky preparation difficult to understand as follows as the reference substance of related substance:
| Lot number | Impurity compound | Impurity with respect to impurity compound retention time 2.0 |
| 101201(25mg) | 0.001％ | 0.005％ |
| 101202(25mg) | 0.002％ | 0.004％ |
| 101203(25mg) | Do not detect | 0.004％ |
| 101101(20mg) | 0.002％ | 0.003％ |
| 101102(20mg) | Do not detect | 0.004％ |
| 101201(20mg) | 0.003％ | 0.005％ |
Embodiment 5 impurity compounds 4,4-two (6,10-dihydroxyl-7-chloro-pyridyl)-propyl carbinol is measured the related substance that replaces lucky preparation difficult to understand as the reference substance of related substance
Replace lucky tablet related substance quality standard difficult to understand:
The preparation of need testing solution: lucifuge operation, get the development of preparation content, mix, precision takes by weighing in right amount (being equivalent to approximately Tegafur 50mg), put in the 100ml measuring bottle, add acetonitrile-water (3: 7) 30ml, ultrasonic 5min (temperature control on the rocks) takes out and is placed to room temperature, add acetonitrile-water (3: 7) to scale, shake up, filter, get subsequent filtrate as trial-product (facing with now joining).
Get the about 14.5mg of impurity compound reference substance, the about 50mg of Tegafur reference substance, accurately weighed, put in the 100ml measuring bottle, add acetonitrile-water (3: 7) and dissolve and be diluted to scale, shake up; Precision is measured 1ml, puts in the 100ml measuring bottle, adds acetonitrile-water (3: 7) and dissolves and be diluted to scale, shakes up, in contrast product solution.
Chromatographic condition: be weighting agent with octadecylsilane chemically bonded silica, take phosphate buffered saline buffer-methyl alcohol (60: 40) as moving phase, the detection wavelength is 220nm, column temperature: 35 ℃, the resolution of Tegafur and impurity compound chromatographic peak is not less than 10.0; Get reference substance solution 15 μ l injection liquid chromatographies, regulate detection sensitivity, make the peak height of the chromatographic peak of impurity compound be about the 20%-25% of full range, precision is measured need testing solution and each 15 μ l of reference substance solution again, the injection liquid chromatography, the record color atlas is to 3 times of impurity compound chromatographic peak retention time, in the color atlas of need testing solution if any impurity peaks, take impurity compound as reference substance, press external standard method with calculated by peak area, impure compound must not be greater than 0.5% of Tegafur labelled amount, and containing retention time with respect to impurity compound and be 2.0 impurity must not be greater than 0.5% of Tegafur labelled amount.
Foreign matter content
Impurity compound is measured for its related substances check result of lucky preparation difficult to understand as follows as the reference substance of related substance:
| Lot number | Impurity compound | Impurity with respect to impurity compound retention time 2.0 |
| 101204(25mg) | 0.003％ | 0.004％ |
| 101205(25mg) | 0.001％ | 0.003％ |
| 101206(25mg) | Do not detect | 0.004％ |
| 101103(20mg) | 0.001％ | 0.003％ |
| 101104(20mg) | Do not detect | 0.004％ |
| 101202(20mg) | 0.002％ | 0.002％ |
Claims (4)
1. compound 4,4-two (6,10-dihydroxyl-7-chloro-pyridyl)-propyl carbinol, chemical structural formula is as follows:
2. compound 4, the preparation method of 4-two (6,10-dihydroxyl-7-chloro-pyridyl)-propyl carbinol may further comprise the steps:
A, with Tegafur, gimeracil, oteracil potassium as reaction-ure mixture, 50-60 soluble in water ℃ stirring reaction 12-72 hour, by HPLC and HPLC-MS analysis monitoring reaction process, react complete solvent evaporated, get the white solid thing;
B, a is reacted the solid resultant use the preparation of preparative liquid phase system, removing foreign matter compound from reaction mixture;
Chromatographic condition and system suitability: use the dynamic axial compression chromatographic column system, internal diameter 80mm is take octadecylsilane chemically bonded silica as weighting agent; Take 7: 3 water-acetonitriles of volume ratio as moving phase; The detection wavelength is 280nm; Flow velocity is 200ml/min; Theoretical plate number is calculated by the naphthalene peak and is not less than the 6000/25cm effective column length;
Get for lucky sample crude product difficult to understand, take by weighing 15g, put in the 2000ml beaker, measure 1000ml moving phase, jolting makes dissolving, and with 0.45 μ m membrane filtration, getting filtrate is sample to be separated; Each sample introduction 100ml gathers color atlas, and retention time is by the peak of 6.79min and is wanted impurity peaks, the liquid of collection 600mV 600mV to the peak before the peak, and concentrate drying gets the target impurity pure compounds.
3. compound 4,4-two (6,10-dihydroxyl-7-chloro-pyridyl)-propyl carbinol for the inspection of lucky preparation related substance difficult to understand the time as the purposes of impurity reference substance.
4. use of a compound according to claim 3 is characterized in that the quality standard when checking for lucky preparation related substance difficult to understand is:
The preparation of need testing solution: the lucifuge operation, get the development of preparation content, mix, precision takes by weighing in right amount, be equivalent to approximately Tegafur 50mg, put in the 100ml measuring bottle, add 3: 7 acetonitrile solution 30ml of volume ratio, ultrasonic 5min, taking-up is placed to room temperature, adds 3: 7 acetonitrile solution of volume ratio to scale, shakes up, filter, get subsequent filtrate as trial-product;
The preparation of reference substance solution: get the about 14.5mg of impurity compound reference substance, the about 50mg of Tegafur reference substance, accurately weighed, put in the 100ml measuring bottle, add the dissolving of 3: 7 acetonitrile solution of volume ratio and be diluted to scale, shake up; Precision is measured 1ml, puts in the 100ml measuring bottle, adds the dissolving of 3: 7 acetonitrile solution of volume ratio and is diluted to scale, shakes up, in contrast product solution;
Chromatographic condition: be weighting agent with octadecylsilane chemically bonded silica, take 60: 40 phosphate buffered saline buffer-methyl alcohol of volume ratio as moving phase, the detection wavelength is 220nm, column temperature: 35 ℃, the resolution of Tegafur and impurity compound chromatographic peak is not less than 10.0; Get reference substance solution 15 μ l injection liquid chromatographies, regulate detection sensitivity, make the peak height of the chromatographic peak of impurity compound be about the 20%-25% of full range, precision is measured need testing solution and each 15 μ l of reference substance solution again, the injection liquid chromatography, the record color atlas is to 3 times of impurity compound chromatographic peak retention time, in the color atlas of need testing solution if any impurity peaks, take impurity compound as reference substance, press external standard method with calculated by peak area, impure compound must not be greater than 0.5% of Tegafur labelled amount, containing retention time with respect to impurity compound and be 2.0 impurity must not be greater than 0.5% of Tegafur labelled amount, containing other single contaminants must not be greater than 0.1% of Tegafur labelled amount, and each impurity summation must not be greater than 0.5%.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107089942A (en) * | 2017-05-27 | 2017-08-25 | 山东省医学科学院药物研究所 | Tegafur, gimeracil and oteracil potassium impurity B CB preparation method |
| CN108169399A (en) * | 2017-12-15 | 2018-06-15 | 山东金城医药化工有限公司 | The separation method of impurity in ethyl demethylaminothiazolyloximate crude product |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070036717A1 (en) * | 2005-08-11 | 2007-02-15 | The Kitasato Gakuen Foundation | Chemoradiotherapy with TS-1/camptothecins |
| WO2007043531A1 (en) * | 2005-10-07 | 2007-04-19 | Celestar Lexico-Sciences, Inc. | Genetic marker for use in diagnosis of sensitivity to anti-tumor agent or concurrent chemoradiation therapy, and use thereof |
| US20070254045A1 (en) * | 2006-04-28 | 2007-11-01 | Japan As Rep. By President Of National Cancer Ctr. | Method for treating head and neck cancer |
| CN101711765A (en) * | 2009-10-31 | 2010-05-26 | 山东新时代药业有限公司 | Dispersing tablet containing tegafur, gimeracil and oteracil potassium |
| CN101721417A (en) * | 2009-12-21 | 2010-06-09 | 深圳海王药业有限公司 | Entogastric lingering floating slow-release tablet for treating malignant tumor of gastrointestinal tract |
| CN101843621A (en) * | 2009-12-30 | 2010-09-29 | 山东新时代药业有限公司 | TS-1 granules and preparation method thereof |
-
2011
- 2011-09-10 CN CN201110280928.6A patent/CN102993087B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070036717A1 (en) * | 2005-08-11 | 2007-02-15 | The Kitasato Gakuen Foundation | Chemoradiotherapy with TS-1/camptothecins |
| WO2007043531A1 (en) * | 2005-10-07 | 2007-04-19 | Celestar Lexico-Sciences, Inc. | Genetic marker for use in diagnosis of sensitivity to anti-tumor agent or concurrent chemoradiation therapy, and use thereof |
| US20070254045A1 (en) * | 2006-04-28 | 2007-11-01 | Japan As Rep. By President Of National Cancer Ctr. | Method for treating head and neck cancer |
| CN101711765A (en) * | 2009-10-31 | 2010-05-26 | 山东新时代药业有限公司 | Dispersing tablet containing tegafur, gimeracil and oteracil potassium |
| CN101721417A (en) * | 2009-12-21 | 2010-06-09 | 深圳海王药业有限公司 | Entogastric lingering floating slow-release tablet for treating malignant tumor of gastrointestinal tract |
| CN101843621A (en) * | 2009-12-30 | 2010-09-29 | 山东新时代药业有限公司 | TS-1 granules and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 孙亮: "《STN》", 17 June 2014 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107089942A (en) * | 2017-05-27 | 2017-08-25 | 山东省医学科学院药物研究所 | Tegafur, gimeracil and oteracil potassium impurity B CB preparation method |
| CN107089942B (en) * | 2017-05-27 | 2019-08-06 | 山东省医学科学院药物研究所 | The preparation method of tegafur, gimeracil and oteracil potassium impurity B CB |
| CN108169399A (en) * | 2017-12-15 | 2018-06-15 | 山东金城医药化工有限公司 | The separation method of impurity in ethyl demethylaminothiazolyloximate crude product |
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